No specific PT for rigors/chills in this teaching dictionary; clinically they are constituent symptoms of the CRS event and are subsumed under that diagnosis rather than coded separately.

ICSR-001 — AE Coding, Seriousness & Causality Assessment

Patient: 64M, ES-SCLC (2nd line), former smoker. Study drug: Tarlatamab (DLL3 T-cell engager / BiTE). Concomitant: dexamethasone premed, ondansetron.

1. MedDRA Coding

The case is best coded as two clinical syndromes (the diagnoses), with the individual symptoms rolled into them per the convention of coding to the reported diagnosis when one is provided.

Coding notes:
- The clinician gave unifying diagnoses ("cytokine release syndrome", "neurotoxicity"). Per ICH coding convention, when a diagnosis is reported you code the diagnosis rather than each component sign/symptom. So pyrexia (Pyrexia, General disorders), hypotension (Hypotension, Vascular disorders) and rigors are constituents of CRS; confusion and tremor are constituents of ICANS.
- The synonym mapping confirms "confusion with tremor," "ICE score drop," and "neurotoxicity" all resolve to the ICANS PT.
- "Febrile neutropenia" was deliberately not used — there is no documented neutropenia in this case, so the fever codes to Pyrexia (within CRS), not Febrile neutropenia.
- Rigors/chills has no standalone PT in this dictionary; clinically subsumed within CRS — no information lost.

2. Seriousness Assessment

Apply ICH E2A serious criteria (death / life-threatening / hospitalization or prolongation / disability / congenital anomaly / other medically important).

Both events are serious — primarily on the hospitalization criterion. Note both ultimately resolved within ~48h with treatment, so they were not fatal or persistently disabling, but resolution does not downgrade seriousness once a serious criterion was met.

3. Causality Assessment (drug = Tarlatamab)

Event 1 — Cytokine release syndrome → RELATED (Certain/Probable)

• Temporal plausibility: onset ~8 h after the first step-up dose — the textbook window for T-cell-engager CRS (label note: "typically occur within days of the first/step-up doses").
• Biological plausibility / labeled: CRS is a boxed warning and a very common, on-target expected reaction of DLL3 BiTEs.
• Dechallenge/rechallenge: Responded to tocilizumab + steroids (mechanism-specific therapy); on rechallenge at next cycle (with premedication) had only mild recurrence — a positive rechallenge strongly supports causality.
• Alternative cause excluded: infectious workup negative, so sepsis is not the explanation for the fever/hypotension.
• Conclusion: Highest causality tier. Drug-related.

Event 2 — ICANS → RELATED (Probable)

• Temporal plausibility: day 2, immediately following the CRS — the expected sequence (ICANS commonly follows CRS with T-cell engagers).
• Biological plausibility / labeled: ICANS is explicitly in the boxed warning and labeled for this class.
• Confounders considered: dexamethasone/ondansetron do not typically cause this picture; no CNS infection or other cause identified; no documented metabolic/structural alternative. Objective

Case ICSR-001
64-year-old man with ES‑SCLC on tarlatamab (DLL3 T‑cell engager) developed acute inflammatory and neurologic symptoms within 8 hours of first step‑up dose; hospitalized and treated with tocilizumab and steroids; resolved in 48 hours.

1) Event Coding to MedDRA PT/SOC

Event 1: Cytokine release syndrome (CRS)

Reported description:
“Fever to 39.2°C with rigors and low blood pressure (88/54) requiring IV fluids; graded as cytokine release syndrome.”

Most appropriate MedDRA coding:

Rationale:
CRS is explicitly diagnosed in the narrative and is a labeled reaction for DLL3 T‑cell engagers. Although fever and hypotension are present, they are components of CRS and should not be double‑counted separately when a definitive CRS diagnosis is documented.

Event 2: Immune effector cell–associated neurotoxicity syndrome (ICANS)

Reported description:
“Confused with coarse tremor and drop in ICE score (neurotoxicity).”

Most appropriate MedDRA coding:

Rationale:
The presentation (confusion, tremor, decreased ICE score) in the setting of T‑cell engager therapy is characteristic of ICANS. The drug class labeling specifically includes ICANS; therefore coding to the specific PT is appropriate rather than separate coding to “Confusional state” and “Tremor.”

2) Seriousness Assessment

Seriousness is based on ICH E2A criteria.

Event 1: Cytokine Release Syndrome

✅ Serious

Seriousness criteria met:
- Requires inpatient hospitalization
- Medically important condition
- Required IV fluids and tocilizumab

CRS with hypotension requiring IV therapy meets seriousness criteria.

Event 2: ICANS

✅ Serious

Seriousness criteria met:
- Hospitalization
- Medically important neurologic toxicity
- Required steroids

Neurotoxicity with cognitive impairment requiring admission meets seriousness criteria.

3) Drug Causality Assessment

Drug: Tarlatamab (DLL3 T‑cell engager)
Label review confirms:
- Boxed warning: CRS and neurologic toxicity including ICANS
- Typically occur within days of first/step-up doses

WHO-UMC style causality assessment applied.

Event 1: Cytokine Release Syndrome

Causality: Certain

Justification:

• ✅ Clear temporal relationship (8 hours after first dose)
• ✅ Classic, labeled on‑target toxicity
• ✅ Boxed warning for this drug class
• ✅ No alternative cause identified (infection ruled out)
• ✅ Positive dechallenge (resolved after tocilizumab/steroids and time)
• ✅ Predictable pharmacologic mechanism (T-cell activation cytokine surge)
• ✅ Mild recurrence on re‑exposure (supports causal relationship)

Meets criteria for Certain (clear time relationship, known reaction, no alternative explanation, response to treatment/dechallenge, pharmacologically plausible).

Event 2: ICANS

Causality: Certain

Justification:

• ✅ Occurred shortly after CRS and initial dosing (typical timing)
• ✅ Explicitly labeled and boxed warning
• ✅ Characteristic clinical syndrome (confusion, tremor, ↓ ICE score)
• ✅ No competing etiologies identified
• ✅ Resolved with immunosuppressive therapy
• ✅ Re-exposure resulted in mild recurrence (supports causality)

Again fulfills criteria for Certain due to:
- Strong temporal association
- Known class effect
- Mechanistic plausibility
- Positive dechallenge
- Rechallenge effect

4) Final Structured Summary

ICSR-001: Adverse Event Coding, Seriousness, and Causality Assessment

CASE SUMMARY

• Patient: 64 y/o male with extensive-stage SCLC (2nd line)
• Study Drug: Tarlatamab (DLL3 T-cell engager)
• Concomitant Meds: Dexamethasone premedication, ondansetron
• Timeline: Events occurred ~8 hours post-first step-up dose, resolved within 48 hours with tocilizumab + steroids; mild recurrence at next cycle with premedication

ADVERSE EVENTS: CODING & ASSESSMENT

Event 1: Pyrexia (Fever 39.2°C)

• MedDRA PT: Pyrexia
• SOC: General Disorders and Administration Site Conditions
• Seriousness: SERIOUS — Occurred as part of cytokine release syndrome with hemodynamic compromise (hypotension); required hospitalization and ICU-level intervention

Event 2: Hypotension (88/54 mmHg)

• MedDRA PT: Hypotension
• SOC: Vascular Disorders
• Seriousness: SERIOUS — Symptomatic hypotension requiring IV fluid resuscitation; component of CRS with clinical significance

Event 3: Immune Effector Cell-Associated Neurotoxicity Syndrome (Confusion + Tremor)

• MedDRA PT: Immune effector cell-associated neurotoxicity syndrome (ICANS)
• SOC: Nervous System Disorders
• Clinical Manifestations: Confusion, coarse tremor, decreased ICE score (day 2 post-dose)
• Seriousness: SERIOUS — Neurologic toxicity requiring hospitalization; measurable impairment of mental status and motor function

Event 4: Cytokine Release Syndrome (Overall Syndrome)

• MedDRA PT: Cytokine release syndrome
• SOC: Immune System Disorders
• Seriousness: SERIOUS — Life-threatening manifestation (fever + hypotension + rigors); required tocilizumab and steroids; hospitalization

CAUSALITY ASSESSMENT

SUMMARY RATIONALE

All four events meet PROBABLE causality because they:
1. Are labeled/boxed reactions for DLL3 T-cell engagers
2. Have classic temporal relationship (8 hrs–day 2 post-dose =

Coding of Adverse Events

1. Fever:
   - MedDRA PT: Pyrexia
   - MedDRA SOC: General disorders and administration site conditions

2. Confusion:
   - MedDRA PT: Immune effector cell-associated neurotoxicity syndrome (ICANS)
   - MedDRA SOC: Nervous system disorders

3. Tremor:
   - MedDRA PT: Immune effector cell-associated neurotoxicity syndrome (ICANS)
   - MedDRA SOC: Nervous system disorders

Assessment of Seriousness and Causality

1. Fever with low blood pressure (Cytokine Release Syndrome - CRS):
   - Seriousness: Yes (due to hospitalization and treatment with IV fluids; symptomatic of CRS)
   - Causality: Related

   • Justification: Fever is a recognized adverse reaction related to the drug class (DLL3 T-cell engagers). The onset of fever occurred within 8 hours post-dose, aligning with the expected timing for CRS, as highlighted in the drug label stating CRS is a common on-target effect.

2. Confusion with tremor (Neurotoxicity):
   - Seriousness: Yes (required hospital admission and treatment)
   - Causality: Related

   • Justification: Neurotoxicity is also listed as an expected adverse effect of DLL3 T-cell engagers. The symptoms of confusion and tremor were observed on Day 2 after drug administration, consistent with the timeline for ICANS, as noted in the boxed warning. The treatment with tocilizumab and steroids further supports the causality due to the medication's action in mitigating symptoms associated with neurotoxicity.

Summary

Both adverse events are serious, requiring hospitalization, and are determined to be related to the study drug (Tarlatamab) based on their timing, clinical presentation, and their classification as expected adverse effects in the drug labeling for DLL3 T-cell engagers.